Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435

Bioorg Med Chem Lett. 2002 Nov 18;12(22):3333-6. doi: 10.1016/s0960-894x(02)00737-0.

Abstract

Several 5,12-diazachrysen-6-ones and 5,6,11-triazachrysen-12-ones were synthesized with varied substituents at the 5- or 11-position, respectively. Each compound was evaluated for its potential to stabilize the cleavable complex formed with TOP1 and DNA. Two analogues with very potent TOP1-targeting activity, 3a and 4a, exhibited cytotoxic activity with IC(50) values at or below 2nM against RPMI8402. Compound 3a was active in vivo by either ip or po administration in the human tumor xenograft athymic nude mice model.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Aza Compounds / administration & dosage
  • Aza Compounds / chemical synthesis
  • Aza Compounds / pharmacology
  • Cell Division / drug effects
  • Chrysenes / administration & dosage
  • Chrysenes / chemical synthesis
  • Chrysenes / pharmacology*
  • DNA / metabolism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy*
  • Topoisomerase I Inhibitors*
  • Transplantation, Heterologous
  • Treatment Outcome
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Aza Compounds
  • Chrysenes
  • Enzyme Inhibitors
  • Topoisomerase I Inhibitors
  • DNA